Summary: A module of negative feedback regulators defines
growth factor signaling
Ido Amit1,9, Ami Citri1,8,9, Tal Shay2, Yiling Lu3, Menachem Katz1, Fan Zhang3, Gabi Tarcic1, Doris Siwak3,
John Lahad3, Jasmine Jacob-Hirsch4, Ninette Amariglio4, Nora Vaisman5, Eran Segal6, Gideon Rechavi4,
Uri Alon7, Gordon B Mills3, Eytan Domany2 & Yosef Yarden1
Signaling pathways invoke interplays between forward signaling and feedback to drive robust cellular response. In this study, we
address the dynamics of growth factor signaling through profiling of protein phosphorylation and gene expression, demonstrating
the presence of a kinetically defined cluster of delayed early genes that function to attenuate the early events of growth factor
signaling. Using epidermal growth factor receptor signaling as the major model system and concentrating on regulation of
transcription and mRNA stability, we demonstrate that a number of genes within the delayed early gene cluster function as
feedback regulators of immediate early genes. Consistent with their role in negative regulation of cell signaling, genes within
this cluster are downregulated in diverse tumor types, in correlation with clinical outcome. More generally, our study proposes
a mechanistic description of the cellular response to growth factors by defining architectural motifs that underlie the function
of signaling networks.
Cells respond in a stereotypic and highly reproducible manner to
external stimuli. A major focus of current research is elucidation of the
mechanisms underlying the regulation of this response. In the past,
considerable effort was invested in characterizing `forward-signaling'
components activated by external stimuli, with successful identifica-
tion of proteins involved in signaling cascades and immediate-early